One childhood stressor - child maltreatment - represents a serious public health concern. In 2007, over 3 million children were referred to child protection service agencies for suspected maltreatment in the United States and about 794,000 were determined by state and local child protective service agencies to be victims of maltreatment (DHHS, 2009). Increasing evidence shows that childhood physical and sexual abuse and (more recently) neglect have extensive short- and long-term consequences across multiple domains, including psychiatric, social, emotional, behavioral, academic, and physical functioning, and developmental time points. The associated costs to society have been estimated at billions of dollars annually. At the same time, the negative sequelae of childhood victimization are not inevitable. While explanations for these different outcomes remain unknown, research has begun to examine factors that might buffer or protect maltreated children from negative consequences. Recent research has reported significant interactions between childhood maltreatment and genetic variation in predicting psychological and behavioral outcomes, including violence and antisocial behavior, depression, anxiety, suicidality, alcoholism, and substance use. The overarching goal of the proposed research is to test three competing models of the processes whereby child abuse and neglect lead to mental and physical health consequences in adulthood. The research proposed here represents a continuation of a longitudinal study begun in 1986 with a large group of documented cases of childhood physical and sexual abuse and neglect (ages 0-11) and a comparison group of non-abused and non-neglected children who were matched on the basis of age, sex, race/ethnicity, and approximate family social class and followed up into adulthood with four interviews. We propose to use blood and saliva samples that have already been collected as part of previous waves of the study. Our goal is to identify, genotype, and analyze genetic variants and to determine whether they play a role in the long-term physical and mental health consequences of child abuse and neglect. The proposed research will lead to increased understanding of the multiple pathways through which stressful childhood experiences (such as child neglect and abuse) lead to the development of different mental and physical health outcomes and is in keeping with President Obama's emphasis on health care education and the prevention of negative health outcomes. Determining the interplay between genetic and environmental factors that increase risk for negative physical and mental health outcomes or promote resiliency among abused and neglected children has implications for treatment and prevention efforts for these children. By determining whether a particular environment (such as an abusive or neglectful home) is particularly problematic for children with certain genes, we hope that the proposed research will provide directions for focused interventions. PUBLIC HEALTH RELEVANCE: Child maltreatment, one major source of childhood stress, is a serious public health problem, with about 800,000 substantiated cases of childhood victimization each year. Recent research has reported significant interactions between child maltreatment and genetic variations in predicting psychological and behavioral outcomes. The overarching goal of the proposed research is to test three models that have been proposed to understand the linkages between childhood maltreatment and long-term physical and mental health consequences and, ultimately, may lead to the development of appropriate intervention strategies.